The present invention disclosed herein relates to a hepatocyte nuclear factor 4 alpha (HNF4-α) antagonist and a use thereof, and more specifically, to an antagonist which specifically binds to the ligand binding domain of HNF4-α and inhibits the activity of HNF4-α, and a composition which includes the HNF4-α antagonist as an active ingredient and is for preventing and treating gastric cancer.
Hepatocyte nuclear factor 4 alpha (HNF4-α), being a hepatocyte nuclear factor, is a DNA binding protein which is present in nuclei, abundant in the liver, and known as a transcription factor involved in the control of liver-specific genes. Additionally, HNF4-α is a transcription factor belonging to a steroid receptor family and activates the HNF1-α gene. Although it was reported in a previous study that HNF4-α activates the transcription of a target gene in the non-presence of an exogenous ligand, a later study revealed that a particular fatty acid acyl-CoA activates HNF4-α, thereby controlling the activity of HNF4-α by a particular ligand.
Additionally, it is known that HNF4-α indeed controls the expression of the genes associated with lipid transport, such as microsomal triglyceride transfer protein (MTP), apolipoprotein B (apoB), and apolipoprotein CIII (apoCIII), or the expression of genes associated with glucose metabolism, such as phosphenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). HNF4-α is expressed in the kidneys and intestines as well as in the liver, and is widely associated with energy metabolism in vivo or maintenance of homeostasis, such as synthesis, transport, and secretion of fatty acids and regulation of cell cycle.
HNF4-α is known to control not only the transcription of genes necessary in the processes of metabolism of cholesterol, fatty acids, and glucose and decomposition in the liver, but also the transcription of representative drug-metabolizing enzymes, such as cytochrome P450 2D6 (CYP2D6), cytochrome P450 2B6 (CYP2B6), cytochrome P450 3A4 (CYP3A4), and cytochrome P450 2C9 (CYP2C9).
In fact, it has been acknowledged in mice with the deletion of HNF4-α that there are reductions in the expression of MTP and apo proteins, reduction of serum cholesterol and serum triglycerides in the liver, and reduction in body weight. Therefore, it has been speculated that inhibiting the activity of HNF4-α may render the capabilities of controlling lipid metabolism and glucose metabolism, and may be effectively used to develop an agent for preventing or improving hypertriglyceridemia, fatty liver, and diabetes.
In the conventional art, it was reported that the transcription activity of HNF4-α is inhibited by small heterodimer partner (SHP), which is one of the target proteins of farnesoid X receptor (FXR), and as ligands acting on the HNF4a protein, long-chain fatty acid acyl CoA (palmitoyl CoA, myristoyl-CoA, dodecanoyl-CoA, stearoyl-CoA, linoleoyl-CoA, liolenoyl CoA, eicosapentaenoyl-CoA, docosahexaenoyl-CoA) has been reported.
Japanese Patent Application Publication No. 2008-133247 discloses nitrogenistein, which is an inhibitor of HNF4-α activity for preventing or improving fatty liver or diabetes, International Patent Publication No. WO2002-024227 discloses that HNF4α protein is overexpressed in colorectal tissues and that inhibiting HNF4α protein can inhibit the proliferation of tumor cells, and U.S. Patent Application Publication No. 2010-0286220 discloses the BIM5078 compound as a HNF4-α antagonist.
Meanwhile, gastric cancer, being a malignant tumor occurring in the stomach, includes gastric adenocarcinoma developing on the epithelium of the stomach, a malignant lymphoma developing on the submucosa, myosarcoma, interstitial tumor, etc., but generally refers to gastric adenocarcinoma.
Gastric adeno-carcinoma is the second leading cause of cancer-related death among 700,349 deaths in 2000, and is the fourth most commonly diagnosed cancer in the world. Gastric adeno-carcinoma is considered a single heterogeneous disease having several epidemiological and pathological characteristics. Gastric cancer treatment is based on clinical parameters, such as tumor, node, and metastasis (TNM) staging which determines whether patients should be treated by surgery only or by surgery and chemotherapy. Gastric cancer stage, unlike other cancers such as breast cancer and colorectal cancer, can be clearly distinguished from stage I to stage IV according to the TNM staging system. That is, the survival rate of patients with stage I gastric cancer is 90% or more, while those with stage IV gastric cancer is 20% or less, thus showing a big difference. Based on the staging system described above, gastric cancer can be classified into early gastric cancer, locally advanced gastric cancer, locally advanced invasive gastric cancer, or metastatic gastric cancer, etc.
The present inventors have confirmed through previous studies that HNF4-α is overexpressed in an early stage of gastric cancer to thereby increase the expression of Wnt5α, and have also confirmed that when shRNA is used to inhibit the expression of the HNF4-α gene, or the HNF4-α antagonist is treated, the formation of tumors can be inhibited by controlling the Wnt signal.
Accordingly, while endeavoring to select HNF4-α antagonists for preventing and treating gastric cancer, the present inventors have selected the compounds which can inhibit the activity of HNF4-α by specifically binding to the HNF4-α of the ligand binding domain, and have confirmed that the selected compounds can specifically reduce the expression of Wnt5a and significantly inhibit the growth of gastric cancer, thereby completing the invention.